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Recent study established the role of integrins in keratinocyte growth factor (KGF)-induced oral epithelial adhesion and rete peg elongation. However, how extracellular matrix (ECM) remodeling cooperates with the increased epithelial adhesion during rete peg elongation has yet to be determined. Podosomes are cell-matrix contact structures that combine several abilities, including adhesion and matrix degradation. In the present study, we identified podosome formation at the ventral side of human immortalized oral epithelial cells (HIOECs) upon KGF treatment. Moreover, podosomal components including integrin α6，β4，α3，β1 and MMP14 colocalized with the F-actin-cortactin complex and matrix degradation assays demonstrated the ability of the F-actin-cortactin complex to degrade matrix. Inhibition both of integrin subunits β4 and β1 with specific blocking antibodies and inhibition of Erk1/2 abrogated the KGF-induced podosome formation. Notably, knockdown of integrin subunits β4 and β1 with specific small interfering RNA (siRNA) downregulated the phosphorylation levels of Erk1/2. In contrast, inhibition of both Erk1/2 could upregulate the expression of integrin subunits β4 and β1. These results demonstrate that KGF induces podosome formation via integrin-Erk1/2 signaling in HIOECs, suggesting a novel mechanism by which integrins enhance oral epithelial adhesion and rete peg elongation., (Copyright © 2019. Published by Elsevier Inc.)

The blood-brain barrier (BBB) is located at the brain microvessel level and isolates the brain from the whole body, thus restricting molecule and cell exchanges between cerebral and peripheral compartments. In order to better decipher and understand the BBB physiology and development, and to investigate transport mechanism and toxicity of neuropharmaceuticals, several in vitro BBB models have been developed using animal or human cells, primary or immortalized cells. The aim of this review is to explain to the reader the major criteria required for a pertinent in vitro BBB model and to briefly expose the different models currently available with their characteristics with a special focus on the static models., (© 2017 médecine/sciences – Inserm.)

Several enzymes secreted in the extracellular space, such as matrix metalloproteinases and lysyl oxidase, are internalized and translocated to the nucleus, where they may act as proteases and transcription factors to regulate gene expression and enhance apoptosis. Membrane proteoglycan syndecans, glycosaminoglycans and an anti-angiogenic matricryptin of collagen XVIII have also been identified in the nucleus. The nuclear entry of most extracellular proteins is likely mediated by nuclear localizing sequences. The molecular mechanisms of nuclear import, the physiopathological contexts, which induce it, and the biological roles played in vivo by extracellular proteins and proteoglycans are still underexplored., (© Société de Biologie, 2016.)

Introduction: Epithelial regeneration is a complex process. It can lead to the remodeling of the airway epithelium as in asthma, COPD or cystic fibrosis., Background: The development of in vivo and in vitro models has allowed the analysis of remodeling mechanisms and showed the role of components of extracellular matrix, proteases, cytokines and growth factors. Airway epithelial progenitors and stems cells have been studied in these models. However, their identification remains difficult., Conclusion: Identification and characterization of airway epithelial progenitor/stem-cells, and a better knowledge of the regeneration process may allow the development of new therapeutic strategies for airway epithelial reconstitution., (Copyright © 2013 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Valvular heart diseases represent an important public health burden. With the decrease in the incidence of rheumatic heart disease, calcific aortic stenosis has now become the most common valvular disease in Western countries. Its prevalence increases with age, such that its affects about 4% of the elderly population and it is the most common motive for valve replacement. Several tissue abnormalities were observed in aortic valves from patients suffering from aortic stenosis: presence of large calcium deposits, inflammatory cells, lipids, and neocapillaries as well as extracellular matrix remodeling. The aortic valves show three characteristic layers: the fibrosa composed mainly of collagen bundles, the spongiosa which consists of a proteoglycan matrix, and the ventricularis which contains several elastic lamellae. The components of the extracellular matrix are synthesized by valvular mesenchymal cells. The turn-over of collagen and elastic fibers is low; the other macromolecules are more rapidly synthesized and hydrolysed. Serine proteases such as enzymes of the fibrinolytic system and matrix metalloproteinases play a role in the remodeling of the extracellular matrix. The hydrolysis of adhesive proteins, such as fibronectin, by plasmin triggers the apoptosis of valvular (myo)fibroblasts, a biological process named anoikis. Cellular events and extracellular matrix remodeling thus participate to the evolution of aortic valves towards aortic stenosis., (© Société de Biologie, 2012.)

Our interest, since a number of years, has focalized on the worldwide rapid expansion of the aging population, accompanied by a progressive increase of age-related pathologies. Most of these concern connective tissues, that are rich in extracellular matrix (ECM), such as osteoarticular, cardiovascular and pulmonary diseases. Therefore age-related modifications of connective tissues become of increasing importance for the understanding of these diseases. In this article, we shall recapitulate some of our (and others') experiments on fibronectin, an important matrix glycoprotein mediating cell-matrix interactions. We studied the effect of age on fibronectin biosynthesis and also the effect of UV-radiation. Both conditions, age and radiation, produce a significant increase of fibronectin biosynthesis. Some results, when in vitro aging of skin fibroblasts was studied, exhibited also a passage-dependent regulation of fibronectin biosynthesis. A few studies, quoted in this review, were reported about the effect of age on integrin expression and function. An important finding was that novel biological fragments of fibronectin have proteolytic activities, pro-inflammatory activity in articular tissues, enhance malignant transformation as well as other activities. Proteolytic activity also increases with age-dependent increase of fibronectin fragmentation. This process exhibits positive feedback properties, forming a vicious circle, possibly important for the age-dependent aggravation of connective tissue diseases. Besides these observations, the recent demonstration of fibronectin elasticity suggests its implication in novel biological regulation as for instance mechano-transduction., (© Société de Biologie, 2012.)

Tumor microenvironment is a complex system composed of a largely altered extracellular matrix (ECM) with different cell types that determine the angiogenic response. Upon the influence of hypoxia, tumor cells secrete cytokines that activate stromal cells to produce proteases and angiogenic factors. The proteases degrade the stromal ECM and participate in the release of various ECM fragments, named matrikines or matricryptins, capable to control tumor invasion and metastasis dissemination. We will focus on the matrikines derived from the NC1 domains of the different constitutive chains of basement membrane-associated collagens and mainly collagen IV. The putative targets of the matrikine action are the proliferation and invasive properties of tumor or inflammatory cells, and the angiogenic and lymphangiogenic responses. For example, canstatin, tumstatin and tetrastatin, respectively derived from the NC1 domains of α2, α3 and α4 chains of collagen IV, inhibit in vivo tumor growth in various experimental cancer models. Their anti-cancer activity comprises an anti-proliferative effect on tumor cells and on endothelial cells by induction of cell apoptosis or cell cycle blockade and the induction of a loss of their migratory phenotype. Matrikines constitute a new family of potent anticancer agents that could be used under various therapeutic strategies: i) induction of their overexpression by cancer cells or by the host cells, ii) use of recombinant proteins or synthetic peptides or structural analogues designed from the structure of the active sequences. These matrikines could be used in combination with conventional chemotherapy or radiotherapy to limit tumor progression., (© Société de Biologie, 2012.)

A variety of exogenous and endogenous agents, including toxic compounds, alcohol, drugs and viruses, can cause acute and chronic liver injuries which may lead to inflammation and fibrogenesis. Most hepatocellular carcinomas arise on a fibrotic or cirrhotic liver, and progression of hepatocellular carcinoma is associated with continuous changes in the cellular microenvironment. Extracellular matrix remodelling is a complex process involving synthesis and degradation of matrix components that modulate the fate of cancer cells. Proteases, including matrix metalloproteinases, cleave matrix components and release polypeptide modules with specific biological activities. Knowledge of the cellular and molecular mechanisms involved in extracellular matrix remodelling will open the path to biomarker identification and tailored treatments targeting the liver tumor microenvironment.

Retinoids (active derivatives of vitamin A) were already demonstrated to be important morphogenes and their implication at the placental and fetal level was already established. A new field of research is now developed in order to show their role on fetal membranes constituted by amnion and chorion. To describe the role of retinoids on these membranes, our studies were focused on target gene research. Firstly, all metabolism enzymes needed to vitamin A pathways were demonstrated to be present and active in signal transduction. Secondly, a bioinformatic analysis was performed to assess a list of potential target genes that could be classified in different biological pathways (inflammation, retinoids, hormones, vascularization, extracellular matrix and water homeostasis). Then, it was demonstrated that the gene coding for PLAT, implied in the degradation of extracellular matrix during programmed or premature rupture of membranes, is regulated by retinoids in a two steps mechanism. Finally, preliminary data showed that some aquaporins, which control water transport across membranes, are expressed and regulated by retinoids in the fetal membranes. A disregulation in pathologies like oligo or poly-hydramnios can be anticipated. Improvement of our knowledge about the retinoid implications is a key point in order to obtain a precise and complete documented cartography of the vitamin A (regulating) in amniotic membranes (regulated) that will permit the development of new diagnostic and therapeutic strategies., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The incidence of chronic kidney disease leading to end-stage renal disease has significantly increased and may reach epidemic proportions over the next decade. Regardless of the initial insult, the progression of most forms of renal disease results in tubulo-interstitial fibrosis. This has been closely correlated to the future appearance of renal failure and has therefore been associated with poor long-term prognosis. New molecules and agents to limit the development of tubulo-interstitial fibrosis and slow down the progression towards end-stage renal disease are needed. In the past twenty years, many efforts have been made to understand the mechanisms of tubulo-intersititial fibrosis with the final goal to develop new therapeutic strategies. In this context, this review will focus on the mechanisms and factors involved in the development and the progression of renal fibrosis and will discuss the new promising therapeutic strategies in animal and humans.

The bronchoalveolar epithelium is submitted to numerous mechanical strains. These strains induce a specific cellular activity at the tissue level. This type of activation has been studied in respiratory medicine, mainly in the context of mechanical ventilation and asthma. The phenomenon of mechanotransduction is linked to various epithelial cellular activities such as epithelium repair, extracellular matrix remodelling, inflammatory mediator release and mucociliary regulation. In this review, the main studies related to bronchoalveolar epithelial mechanotransduction are reported to bring a new perspective on this little known biological phenomenon. A better understanding of the physiological and pathological aspects will potentially offer new treatment approaches for bronchial diseases., (Copyright © 2010 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

The word 'matrikine' designates certain peptides derived from partial degradation of extracellular matrix macromolecules and capable of modulating cellular activities. Some matrikines have been shown to inhibit tumor progression and/or neo-angiogenesis, suggesting they may have therapeutic potential. This review examines the main matrikines with anti-tumoral properties, and particularly those originating from basement membrane macromolecules. After a brief description of their discovery and main characteristics, we discuss their mode of production, mechanism of anti-tumor action, and therapeutic potential.

Arterial ageing - arteriosclerosis - is characterised by both thickening and stiffening of the walls of large and medium arteries. The molecular and cellular mechanisms (i.e. endothelial dysfunction, matrix remodelling, ...) involved in this process are complex, and at least in part common to atherosclerotic injury. Arterial stiffness is strongly associated with cardiovascular disease and an increased risk of morbidity and mortality. The aim of this review is to provide an update on the pathophysiology and the biological process of arterial ageing and to underline the main difference with atherosclerosis damage process in particularly during the calcification step.

Epithelial ovarian cancer remains an insidious and fatal gynecological malignancy. They are associated with a poor prognosis mainly due to a late diagnosis and to acquired chemoresistance. Cancer cell environment profoundly influences tumor development. Tumor microenvironment consists of vascular component, stromal fibroblasts, inflammatory cells and extracellular matrix. The multisite development of epithelial ovarian cancer results from molecular and cellular cross-talks between cancer cells, stromal cells and their extracellular matrix environment. These interactions involve cytokines, adhesives molecules, and proteolytic systems. This review points out the importance of micro-ecology in epithelial ovarian cancer development. For this purpose the relationships between cancer cells and their encountered microenvironments are described with suggesting some potential therapeutic perspectives.

It is widely accepted that the development of carcinoma is not only due to somatic mutations in epithelial cells but also is influenced by the tumor microenvironment ie the stroma. The different stroma components produced growth factors, cytokines, the extra cellular matrix and also participated to the recruitment of the endothelial cells necessary for the tumor neovascularisation. The stroma favored the oncogenesis through synergistic reciprocal paracrine signals with the tumor cells. The stroma is determinant for the tumor progression and therefore is an important therapeutic target.

The deterioration of renal function in chronic kidney disease is related to the progression of renal fibrosis, which was long considered unavoidable. Today, the reversibility of renal fibrotic lesions is a reality, although still clinically rare. Because angiotensin II is highly profibrotic, blocking its action effectively protects the kidney, as numerous clinical trials have shown. The development of interstitial fibrosis is secondary to the epithelial-to-mesenchymal transition induced by transforming growth factor (TGF)-beta. Bone morphogenic protein-7 (BMP-7) and hepatocyte growth factor (HGF) induce the reverse transition and thus open up perspectives for treatment. Degradation of the extracellular matrix by matrix metalloproteinases or other enzymes is another therapeutic pathway. Renal regeneration may be promoted by modulation of hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF).

Expression of melanoma invasiveness, ultimately leading to the formation of metastases, requires that cancer cells break through the successive skin barriers (dermo-epidermal junction, dermis) constituted of various extracellular matrix constituents. In order to facilitate their progression, melanoma cells express, in concert with stromal cells, a group of proteolytic systems which degrade this extracellular structures. However, proteolysis of basement membrane, collagen or elastic fibers can uncover cryptic sites or/and liberate matrix fragments whose properties appeared distinct from their intact macromolecule counterparts. Those fragments, called matrikines, are able to empede or to accelerate melanoma progression ex vivo and in vivo. Non-collagenous domains of basement membrane collagens, which behave like potent "matstatins", are seen as potential pharmacological agents in melanoma.

The balance between production and degradation of type I collagen plays a critical role in the development and maintenance of organ and tissue integrity. Its also represents the most crucial element governing the process of tissue repair. TGF-beta, a key player in the physiopathology of tissue repair, enhances type I collagene gene expression. In contrast, TNF-alpha, whose matrix-remodelling function is opposite to that of TGF-beta, reduces type I collagen gene expression. This review focuses on transcriptional regulation of type I collagen by TGF-beta and TNF-alpha, and on the molecular mechanisms that control the antagonistic activity of TNF-alpha against TGF-beta-driven type I collagen gene expression.

MANAGING THE RESPONSIBLE AGENT: Hepatic fibrosis with its end-point, cirrhosis, are the principle complications responsible for morbidity and mortality in chronic liver diseases. It is therefore important to address the question of whether these lesions can disappear, once installed in the liver. Regression can only occur when the agent responsible for the fibrosis (virus, alcohol, poison, iron, autoantibodies, etc) is eradicated or controlled. THE FORMS OF REGRESSION: Once the agent controlled, regression of fibrosis can either be spontaneous, a rare situation, although some bona fide cases of fibrosis or even cirrhosis reversion have been reported in the literature, or assisted by specific therapy. It is therefore necessary to take into consideration the development of new treatments based on enhanced knowledge of the mechanisms of fibrosis. THE ACTIVITY AND EFFICACY OF TREATMENTS: These treatments target one of the three following mechanisms: the blockade of hepatic stellate cell activation, enzymatic digestion of fibrous tissue and stimulation of liver cell regeneration. Although these treatments have shown efficacy on experimental models of fibrosis, to date, there are no published results formally confirming the efficacy and safety of these treatments in man.

The degradation of extracellular matrix (ECM) during physio-pathological processes involves, essentially, two proteolytic systems: the plasmin (ogen) system and the matrix metalloproteinase (MMP) family. Enzyme activity necessitates the formation of proteolytic cascades acting in the pericellular environment. Several proteins (proteases, integrins, matrix, inhibitors, activators...) participate to enzyme catalysis forming assemblies within specialized plasma membrane structures (invadopodia, caveolae). MMP-mediated ECM degradation leads to the formation of peptides (matricryptins, matrikins) which, in turn, can modulate MMP expression. MMPs (especially gelatinases) can also activate growth factors as pro TGF beta or liberate those factors from matrix sites. Interaction between matrix and gelatinases was shown to influence enzyme activation through several mechanisms. Finally, thrombospondins 1 and 2, matricellular proteins, can regulate gelatinase A by favoring its endocytosis. Those data emphasize the potential interest of certain matrikins or pseudo-matrikins as therapeutic agents to control cell invasion.

The name matricryptin was proposed by Davis et al. (2000) for enzymatic fragments of extracellular matrix containing exposed matricryptic sites. The exposure of these sites occurred after structural or conformational modifications. Matricryptins derived from non fibrillar collagens (IV, VIII, XV and XVIII) and from matrix metalloproteinase-2 inhibit angiogenesis and tumor growth. Proteolysis of SPARC releases several peptides which exert opposite effects on angiogenesis. Matricryptins derived from glycosaminoglycans also participate in the control of angiogenesis.

THE MECHANISMS OF ACTION ALREADY KNOWN: In vitro, chondroïtin sulfate ACS4-ACS6 have a dose-dependent inhibiting effect on the catabolism of proteoglycanes and collagen. They also stimulate the synthesis of extracellular matrix macromolecules. The existence of a chondrocyte cyto-protector effect and a potentially chondro-protective effect has also been demonstrated. ANOTHER MECHANISM OF ACTION: A new regulation route of chondrocyte metabolism has been proposed in which the Insulin Growth Factor (IGF-1) impedes the catabolic effects of another cytokine, Interleukin 1 (IL-1), by increasing its antagonistic receptor. This control appears essential in the maintenance extracellular matrix homeostasis. CARTILAGE WITH OSTEOARTHRITIS: Chondrocytes from OA cartilage have the capacity to produce more constituting macromolecules of the extracellular matrix. Conversely, these same cells have a greater catabolic capacity. The enhanced activity of IL-1 and the concomitant decrease in its antagonistic receptors leads to the reduction in macromolecule levels in the extracellular matrix, produced in the Cell-associated matrix of OA chondrocytes. ANTI-CATABOLIC EFFECT: It has been demonstrated that ACS4-ACS6 are capable of neutralizing the enhanced catabolic capacity of activated human OA chondrocytes.

Hepatic fibrosis is a scaring process leading to cirrhosis, a major complication of numerous chronic liver diseases. Hepatic stellate cells play a central role in the fibrotic process. After parenchymal or biliary injury, cytokines and growth factors allow the recruitment, proliferation, and activation, of stellate cells toward myofibroblasts, which secrete the extracellular matrix. Fibrosis, resulting from the failure of the balance between synthesis and degradation of extracellular matrix, is an evolutive and potentially reversible process. Histological examination is the main investigation to quantify fibrosis. Serological tests are warranted to allow a non invasive follow up of patients. Development of antifibrotic therapies should soon permit to slow down the evolution toward cirrhosis, limiting the needs for hepatic transplantation.

Elastin is the main protein of elastic fibers and confers the property of elastic recoil to the tissues such as arteries, lung, elastic cartilage,... Elastin synthesis goes through several steps: gene transcription, alternative splicing of pre-mRNA, mRNA translation, hydroxylation of some proline residues of the newly synthesized protein-tropoelastin-, association of with a 67 kDa chaperone protein, secretion of tropoelastin molecules in the extracellular space, and their deposition on the microfibrillar scaffold which contains fibrillin 1, fibrillin 2, MAGP 1 and MAGP 2,.... After the synthesis of cross-links-lysinonorleucine, desmosine, isodesmosine-, elastin becomes insoluble and elastic. The elastogenic pathway is regulated at many levels. The most recently described regulatory mechanism of elastin synthesis is the control of elastin mRNA stability. Elastogenesis is well controlled during development and aging but remains responsive to external factors such as soluble compounds-cytokines, vitamins, hormones,...- and hemodynamic stress. In order to ensure its function, both quantity and quality of elastin should be and should remain optimal in elastic tissues.

Molecular and structural biodiversity characterises dental mineral tissues. Groups of matrix proteins belong specifically to each tissue; amelogenins to enamel, DSPP to dentine and CAP to cementum. A wide group of proteins is also shares with other mineralized tissues such as calcium (calbindins) and phosphate (alkaline phosphatase) handling proteins. Dental tissues organisation is also based on specific cellular programs of morpho-differentiation (polarity) and on expression patterns of proteins implicated in mineralisation. The regulation of gene expression in tooth has been analysed regarding various hormones such as vitamin D in a first step and recently transcription factors (Osf-2/Cbfa1/Aml3). Other molecular families encoded by divergent homeobox genes (Msx and Dlx) are implicated in the determinism of this gene regulation and of early development. Genetic and hormonal abnormalities of dental mineralized tissues should now be interpreted thanks to the recent availability of cellular models and of odontogenic protein promoter structure.

Matrix metalloproteinases (MMPs) are major proteolytic enzymes that are involved in extracellular matrix (ECM) turn over. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) cleave type IV collagen, which is an important constituent of basement membrane. These enzymes play an important role in normal tissue homeostasis, but imbalance between MMPs and their tissue inhibitors (TIMPs) is thought to be a critical factor in regulating tissue remodeling. MMP-2 is produced by fibroblasts, endothelial, and epithelial cells, while MMP-9 is mainly produced by inflammatory cells. The role of MMPs was investigated through biochemical analysis or in situ expression, in the pathogenesis of two chronic inflammatory airway diseases, asthma and nasal polyposis. Both are characterized with the accumulation of active inflammatory cells, matrix remodeling and epithelial changes. Increased levels of MMP-9 and TIMP-1 were found in asthmatic subjects and NP. In NP, MMP-9 expression was detected in epithelial, endothelial and inflammatory cells. In this setting, MMP-9 could play a crucial role in the transmigration of basement membrane components by inflammatory cells leading to inflammatory cell accumulation and maintenance of inflammation in airway. Moreover, MMP-9 may contribute to cell migration, an important mechanism involved in the repair of the respiratory epithelium.

Brain metastasis results from complex interactions between host cells and primitive tumor cells. An analysis of the molecular pathways at the cellular level is provided in this review of the literature. The principal new therapeutic modalities are directly based on our comprehension of those molecular biology hypothesis.

The hepatic extracellular matrix is involved in both the stability of liver architecture and the hepatic function. Fibrogenesis occurs during various chronic liver diseases. It is the consequence of an imbalance between synthesis, deposition and degradation of extracellular matrix components leading to fibrosis and, then, cirrhosis. Hepatic stellate cells are the main source of extracellular matrix components in fibrogenesis. Among the factors involved in fibrogenesis, transforming growth factor beta 1 plays a central role. The vascular and cellular consequences of liver fibrogenesis require new specific diagnostic and therapeutic strategies.

Matrix metalloproteases represent a family of proteases secreted as latent inactive enzymes able to degrade the majority of extracellular matrix components. These enzymes are overexpressed during several pathological tissue remodelings including tumor progression and tumor invasion. It was indeed classically admitted that matrix metalloproteases involved in tumoral progression were preferentially expressed by cancerous cells. Our studies on gelatinase A and stromelysin-3 have, however, demonstrated that their messenger RNAS are detected in fibroblasts of the peritumoral stroma in human mammary carcinoma and not in the cancerous cells themselves. By immunohistochemistry, we have detected gelatinase A in the cytoplasm of fibroblasts and at the surface of the tumor cells. This membrane localization of the protein could result from its binding, following secretion by the neighbouring stromal cells, to a specific binding site expressed at the surface of the carcinoma cells. These cells are indeed able to induce an increased proteolytic activity by enhancing the transcription of these enzymes by peritumoral fibroblasts. These enzymes represent therefore potential targets for the development of new therapeutic strategies.

The mammary gland underwent during pregnancy morphological, histological and physiological modifications that ensure the lactation in the post-partum. On the morpho-histological side, the epithelial growth and the milk synthesis during pregnancy allow secondary the lactation. The physiological modifications, beside the endocrines factors such as prolactin, estrogens, progesterone or growth hormone, lead to an auto-paracrines interactions involving the growth factors and the molecules synthetized by the extracellular matrix.

Varicose vein walls differ from normal venous walls by an important loss of their collagen content and an increase of their glycosaminoglycan content, essentially of hyaluronan. The decrease in fibrous protein content can be attributed to increased proteolytic (collagenolytic) activity as well as to free radicals. Glycosaminoglycan increase reflects a disregulation of the normal program of matrix biosynthesis by the cells of varicose vein wall, essentially smooth muscle cells. Some flavonoid drugs are capable of correcting these deviations by decreasing proteolytic attack on fibrous proteins and the accumulation of proteoglycans and hyaluronan. These effects, due to interactions between flavonoid drugs and the cells and fibrous proteins of the venous wall differ according to the nature of such drugs. A hypothesis is proposed to explain these differences in the intensity of action of flavonoid drugs with apparently closely related structures, based on the conformation of these drugs and their interaction with the triple helical structure of collagen fibers as well as with the cell membranes.

Does the c-ets 1 protooncogene take part in the regulation of tumor angiogenesis? The formation of new blood vessels is an essential process in embryonic development and wound healing, for tumor growth and metastasis. In situ hybridization studies have revealed that the protooncogene c-ets 1 is expressed in endothelial cells at the beginning of blood vessel formation, in normal and pathological conditions. C-ets 1 encodes a transcription factor, a protein which binds specifically to DNA and which regulates the transcription of genes containing these specific binding sequences in their promotors. Thus in vitro experiments suggest that c-ets 1 may activate the transcription of genes encoding collagenase 1, stromelysine 1 and urokinase plasminogen activator, proteases involved in extracellular matrix degradation. A working hypothesis is that c-ets 1 takes part in regulating angiogenesis by controlling the transcription of these genes whose activity is necessary for the migration of endothelial cells from preexisting capillaries. This hypothesis is discussed with respect to current experimental evidences and to the complexity of the regulatory network controlling gene transcription and extracellular matrix degradation.

Electron-histochemical visualization of proteoglycans was carried out in the predentine and dentine of rat incisors. Using various techniques proteoglycans were seen to be located between the collagen fibres in predentine, whereas they were observed at the surface of groups of collagen fibres in dentine. The same distribution was found when electron histochemical techniques aiming to visualize phospholipids were used. This co-distribution may play role in the mineralization processes.

The formation of new blood vessels is an essential process in embryonic development and wound healing, for tumor growth and metastasis. In situ hybridization studies have revealed that the protooncogene c-est1 is expressed in endothelial cells at the beginning of blood vessel formation, in normal and pathological conditions. c-ets1 encodes a transcription factor, a protein which binds specifically to DNA and which regulates the transcription of genes containing these specific binding sequences in their promotors. Thus, in vitro experiments suggest that c-ets1 may activate the transcription of genes encoding collagenase 1, stromelysine 1 and urokinase plasminogen activator, proteases involved in extracellular matrix degradation. A working hypothesis is that c-ets1 takes part in regulating angiogenesis by controlling the transcription of these genes whose activity is necessary for the migration of endothelial cells from pre-existing capillaries. This hypothesis is discussed with respect to current experimental evidence and to the complexity of the regulatory network controlling gene transcription and extracellular matrix degradation.

The terminal differentiation of odontoblasts requires the integrity of the cytoskeleton and is controlled by cell-matrix interactions. These interactions implicate both matrix molecules and matrix-associated growth factors. On the one hand, predentin-dentin constituents were found to initiate odontoblast differentiation and to allow the maintenance of this state; TGF-beta or related molecules are implicated. Fibronectin on the other hand can induce the differentiation of second generation odontoblasts and interacts with three high molecular weight proteins present in membrane prepared from dental mesenchymal cells. One of these proteins (165 kDa) was localized on the surface of odontoblasts and is involved in the organization of microfilaments. Two main axes of research will have to be developed in the future in order to understand how matrix molecules and growth factors interactions can be modulated in time and space by epithelial and mesenchymal cells, and how such modulations can affect the phenotype of these cells.

The cancer stroma is made of cellular and non cellular formations which grow along with cancer cells to build up a tumor. It comes from inflammatory cells and mesenchymal tissue which are mobilized and modified by factors released by cancer cells which bring about inflammatory cell accumulation, angiogenesis, fibroblast mitosis and extracellular matrix production. The extracellular matrix is altogether a barrier against and supporting to cancer cells. The extracellular matrix is also involved in the storage of growth factors which are bound to glycosaminoglycans. Although they are antinomic in vitro, peptidic factors released by tumor cells seem to have an enhancing effect on tumor growth in vivo. The cancer invasion is mediated through diverse enzyme activities, particularly proteases, which degrade the matrix whose degradation products can facilitate the tumor progression. The anti-cancer activity which is exhibited in vitro by macrophages and lymphocytes is expressed at a low level by tumor-macrophages and lymphocytes in vivo. The cancer associated inflammation has no particular feature which could help to screening or to follow up patients. Several elements of the cancer stroma could be selected as targets for investigative cancer therapy.

Over recent years, the study of the extracellular matrix (ECM) in the liver has considerably progressed. The application of new biochemical and genetic techniques led to the discovery of 13 different collagen proteins and a growing number of collagen-associated proteins such as fibronectin, laminin and proteoglycans. Many of these proteins have been cloned and sequenced. Progress also includes a better knowledge of the biological roles of ECM components as well as its dynamic remodeling in various pathophysiological conditions. Even if the clinical goal of prophylaxis and therapy of fibrosis remains distant, progress can be anticipated in the near future as basic processes are being elucidated.

Extracellular matrix has a variety of biological effects on cells, including increased cell adhesion, migration, division and differentiation. Cells are also regulated by soluble factors such as cytokines. We have investigated the binding of interferon-gamma to basement membrane. Interferon-gamma binds basement membrane with a high affinity (kD = 1.5 x 10(-9) M). The binding site is located on the glycosaminoglycan part of the heparan sulfate proteoglycan. This result suggests that extracellular matrix interacts with interferon-gamma and could modulate the cellular response to such factors.

Chemotherapeutic assays, using nitrosoureas, performed on tumor bearing rats have shown a regression of local tumor, accompanied with an amplification of pulmonary metastases, demonstrating that the treatment of metastasis differs from the treatment of a local tumor. Cells organizing a tumor are heterogeneous for their drug resistance, and for a series of properties including their ability to form metastasis. Metastatic cells have to leave the tumoral tissue, to traverse biological barriers, to resist to immune system, to implant and growth in the target tissue. An experimental model has been used to characterize metastatic cells. Metastatic potential has been defined as the ability to invade lungs. Highly metastatic cloned cell lines, such as subline 6, were strongly stimulated to proliferate by EGF, expressed fibronectin, actively degraded the extracellular matrix, rapidly attached to endothelial vascular cells, and resisted to natural killer lymphocytes. Inversely, weakly metastatic lines, such as subline 8, were preferentially stimulated by FGF and EDGF, poorly expressed fibronectin, did not degrade extracellular matrix, slowly attached to vascular cells, and were killed by NK lymphocytes. Studies on a large series of clones showed a diversity between them, and that no one property was determinant. Modulation of these characters by growth factors, hormones and immune state of the host is discussed, and leads to conclude that the expression of metastatic potential of a tumor depends on genetically defined characters and also on influences excerted by the host.